The anterior pituitary gland is a small structure located at the base of the brain. Its growth and function are tightly regulated by hypothalamic influences and negative feedback by circulating peripheral hormones. The thyrotrope cell represents one of the cells in the anterior pituitary and its function is to produce thyrotropin which is secreted into the circulation and regulates the growth and function of the thyroid gland which produces the thyroid hormones. Thyrotrope cell function is, in turn, regulated by hypothalamic hormones (TRH and SRIF) and the circulating levels of thyroid hormones (T3 and T4). If the thyroid gland is removed by disease or ablative therapies, the thyrotrope cells proliferate and produce excessive amounts of TSH. This cell type specific proliferation is a unique response since other pituitary cell types do not undergo similar changes in comparable circumstances. Furthermore, prolonged and unrestrained thyrotrope proliferation can enlarge the entire pituitary gland and produce serious compressive consequences to surrounding nonthyrotrope pituitary cells and other brain structures. Little is known about thyrotrope proliferation and its response to thyroid hormone at the molecular or cellular level. The purpose of this grant application is to carry out a comprehensive analysis of these events at the molecular level. Our preliminary data has indicated that multiple selected pathways regulating the cell cycle in thvrotropes are distinct from other cell models. Our first aim will be to extend these observations to in vitro models and to carefully define the unique cascade of events that leads to inhibition of proliferation by thyroid hormone. Our second aim will be to define those events that lead to proliferation by both in vitro and in vivo abrupt withdrawal of thyroid hormones. Our third aim will use the in vitro models to precisely define which growth factors, their receptors, and cell cycle molecules are essential for thyroid hormone regulation using overexpression and inhibition by antisense technology. Our fourth aim will utilize transgenic technology to validate the physiological basis for thvrotrope cell proliferation in the pituitary gland. Finally, our fifth aim will be to reconstitute regulation by thyroid hormone to a unique rapidly proliferating and unregulated model of thyrotrope proliferation that we developed, the alpha-TSH cell. At their conclusion, these studies will develop a body of knowledge that would be directly applicable to the broad field of cell hyperplasia and neoplasia.